Neuropathic pain remains a prevalent, persistent, and debilitating problem. Attempts to elucidate its mechanisms have focused principally on peripheral nerves, dorsal root ganglion, and central nervous system (CNS) neurons. Research efforts have expanded into the burgeoning field of glial/neuronal transmission and CNS immunologic responses to nerve injury. CNS glia display immune cell functions in both normal and pathologic conditions, and there is increasing evidence that neuropathic pain arising from nerve injury has a CNS neuroimmune component (DeLeo & Yezierski (2001) Pain 90:1-6; DeLeo, et al. (2004) Neuroscientist 10:40-52). Spinal glial activation triggers rapid, graded CNS expression of proinflammatory cytokines (including TNF-α, IL-1β, and IL-6) that contributes to the initiation and maintenance of behavioral hypersensitivity after L5 nerve transection (DeLeo & Yezierski (2001) supra; Vuong, et al. (2004) Cell. Microbiol. 6:269-275; Raghavendra, et al. (2004) Neuropsychopharmacology 29:327-334). The onset of proinflammatory cytokine expression correlates with microglial activation and the initiation of behavioral hypersensitivity (Sommer, et al. (1993) J. Neuropathol. Exp. Neurol. 52:223-233; Sommer & Myers (1995) Acta Neuropathol. 90:478-485; Popovich, et al. (1997) J. Comp. Neurol. 377:443-464; Popovich, et al. (1997) J. Neuropathol. Exp. Neurol. 56:1323-1338), and neuroimmune activation in painful neuropathy has been established (Vuong, et al. (2004) supra; Bennett (1999) Proc. Natl. Acad. Sci. USA 96:7737-7738; Bennett (2000) Clin. J. Pain 16:S139-S143). However, the mechanistic links between nerve injury, microglial activation, and the genesis of behavioral hypersensitivity is unclear.
Cells of the innate immune system, including monocytes/macrophages, natural killer cells, neutrophils, and microglia recognize invariant molecular structures of pathogens (termed pathogen-associated molecular patterns, PAMP) by means of stable, genetically conserved, pattern-recognition receptors on the cell surface. The genes producing these receptors are homologous to the Toll gene in Drosophila and are therefore termed Toll-like receptors (Akira & Sato (2003) Scand J. Infect. Dis. 35:555-562). Toll-like receptor 4 (TLR4) is a transmembrane receptor protein with extracellular leucine-rich repeat domains and a cytoplasmic signaling domain. TLR4 expression has been demonstrated in the rodent CNS (Laflamme & Rivest (2001) FASEB J. 15:155-163; Eklind, et al. (2001) Eur. J. Neurosci. 13:1101-1106), where in vivo and in vitro studies show that TLR4 is expressed by microglia (Lehnardt, et al. (2002) J. Neurosci. 22:2478-2486; Lehnardt, et al. (2003) Proc. Natl. Acad. Sci. USA 100:8514-8519). Lipopolysaccharide (LPS, a well known exogenous ligand for TLR4) and potential endogenous ligands for TLR4 (e.g., members of the heat shock protein family and proteoglycans) lead to NF-κB activation and subsequent induction of proinflammatory cytokines (Vabulas, et al. (2002) J. Biol. Chem. 277:15107-15112; Tsan & Gao (2004) Am. J. Physiol. 286:C739-C744). TLR4 gene expression is also significantly increased during all phases of inflammation and is suggested to be related to nerve injury-induced behavioral hypersensitivity (Raghavendra, et al. 2004. Eur. J. Neurosci. 20:467-473). Moreover, increased spinal microglial TLR4 activation correlates with the onset of behavioral hypersensitivity in rats after injury to the L5 spinal nerve, even in the absence of exogenous TLR4 ligands such as LPS (Tanga, et al. (2004) Neurochem. Int. 45:397-407).
Rudofsky, et al. ((2004) Diabetes Care 27:179-183) further teach that type II diabetics that are carriers of polymorphic forms of two TLR4 genes have a lower prevalence of diabetic neuropathy, wherein WO 2005/068442 discloses the use of certain compounds to treat pain in patients without TLR4 polymorphisms.